Inherited mutations of the BRCA1 and BRCA2 genes confer women with a profound predisposition to breast and ovarian cancer. Studies by many groups have characterized germline alterations in >400 independent breast and ovarian cancer families. More than 90% of reported mutations result in truncated proteins due to frameshift, nonsense, or splicing errors. For rapid localization of mutations prior to DNA sequencing, a series of protein truncation and dideoxy-fingerprinting have been developed. As reported with BRCA1, somatic mutations of BRCA2 in sporadic breast and ovarian cancers are extremely rare. In order to identify functional domains of BRCA1 and BRCA2 through evolutionary conservation, we have characterized the mouse and rat homologues of these genes. In addition to the RING finger motif of BRCA1, nuclear localization signals and a carboxy terminal domain with homology to a P53-binding protein are highly conserved. Likewise, a large internal repeat of unknown function has been highly conserved in BRCA2. In contrast, the granin motif, which led to the proposal that these proteins may be involved in a regulated secretory pathway, is poorly conserved in rodents. As an initial step towards development of mouse models for BRCA1 and BRCA2 defects, we have created several targeting vectors for homologous recombination. Repeated attempts to disrupt the RING finger domain of BRCA1 have been unsuccessful. Current efforts are focused on the identification embryonic stem cells with the desired BRCA2 targeting event that will delete portions exon 10 and 11-+.